Long-Term Variability of Distortion-Product Otoacoustic Emissions in Infants and Children and Its Relation to Pediatric Ototoxicity Monitoring.

OBJECTIVE: Distortion-product otoacoustic emissions (DPOAEs) provide a rapid, noninvasive measure of outer hair cell damage associated with chemotherapy and are a key component of pediatric ototoxicity monitoring. Serial monitoring of DPOAE levels in reference to baseline measures is one method for detecting ototoxic damage. Interpreting DPOAE findings in this context requires that test-retest differences be considered in relation to normal variability, data which are lacking in children. This study sought to (1) characterize normal test-retest variability in DPOAE level over the long time periods reflective of pediatric chemotherapy regimens for a variety of childhood ages and f2 primary frequencies using common clinical instrumentation and stimulus parameters; (2) develop level-shift reference intervals; and (3) account for any age-related change in DPOAE level or measurement error that may occur as the auditory system undergoes maturational change early in life. DESIGN: Serial DPOAE measurements were obtained in 38 healthy children (25 females and 13 males) with normal hearing and ranging in age from one month to 10 years at the initial (baseline) visit. On average, children were tested 5.2 times over an observation period of 6.5 months. Data were collected in the form of DP grams, in which DPOAE level was measured for f2 ranging from 1.4 to 10 kHz, using a fixed f2/f1 ratio of 1.22 and stimulus level of 65/55 dB SPL for L1/L2. Age effects on DPOAE level and measurement error were estimated using Bayesian regression of the longitudinal data. The raw and model-based distribution of DPOAE test-retest differences were characterized using means and standard error of the measurement for several ages and f2's. RESULTS: DPOAE test-retest differences for the children in this study are at the high end of those previously observed in adults, as reflected in the associated shift reference intervals. Further, although we observe substantial child-specific variation in DPOAE level, the pattern of age-related changes is highly consistent across children. Across a wide range of f2's, DPOAE level decreases by 3 to 4 dB from 1 to 13 months of age followed by a more gradual decline of <1 dB/year. An f2 of 6 kHz shows the smallest decrease during the early rapid maturation period. DPOAE measurement error is fairly constant with age. It is 3 to 4 dB at most f2's and is greater (indicating poorer reliability) at 1.5, 8, and 10 kHz. CONCLUSIONS: DPOAE level decreases with childhood age, with the greatest changes observed in the first year of life. Maturational effects during infancy and greater measurement error at very low and high f2's affect test-retest variability in children. An f2 of 6 kHz shows minimal maturation and measurement error, suggesting it may be an optimal sentinel frequency for ototoxicity monitoring in pediatric patients. Once validated with locally developed normative data, reference intervals provided herein could be used to determine screen fail criteria for serial monitoring using DPOAEs. Employing state-of-the-art calibration techniques might reduce variability, allowing for more sensitive screen fail criteria.

Serial Monitoring of Otoacoustic Emissions in Clinical Trials.

The purpose of this report is to provide guidance on the use of otoacoustic emissions (OAEs) as a clinical trial outcome measure for pharmaceutical interventions developed to prevent acquired hearing loss secondary to cochlear insult. OAEs are a rapid, noninvasive measure that can be used to monitor cochlear outer hair cell function. Serial monitoring of OAEs is most clearly established for use in hearing conservation and ototoxicity monitoring programs in which they exhibit more frequent and earlier changes compared with pure-tone audiometry. They also show promise in recent human trials of otoprotectants. Questions remain, however, concerning the most appropriate OAE protocols to use and what constitutes a "significant" OAE response change. Measurement system capabilities are expanding and test efficacy will vary across locations and patient populations. Yet, standardizing minimal measurement criteria and reporting of results is needed including documentation of test-retest variability so that useful comparisons can be made across trials. It is also clear that protocols must be theoretically sound based on known patterns of damage, generate valid results in most individuals tested, be accurate, repeatable, and involve minimal time. Based on the potential value added, OAEs should be included in clinical trials when measurement conditions and time permit.

Racial and gender effects on pure-tone thresholds and distortion-product otoacoustic emissions (DPOAEs) in normal-hearing young adults.

This study examined racial and gender effects on behavioral thresholds and distortion-product otoacoustic emissions (DPOAEs) in the same subjects. Pure-tone behavioral thresholds and DPOAEs were measured in 60 young normal-hearing adult subjects (20 Caucasian, 20 Asian, 20 African-American, with ten females and ten males in each group). Behavioral thresholds were measured from 1000 through 16,000 Hz using Békèsy tracking. A DPOAE frequency sweep was measured with primary stimulus levels of L(1)/L(2)=60/45 dB SPL, and an f(2)/f(1) of 1.2 at discrete f(2) frequencies between 2000 through 12,000 Hz for each subject. Significant racial and gender differences in behavioral thresholds were found at 14,000 and 16,000 Hz, with the African Americans and females having the best hearing sensitivity. Based on the current results, similar findings for DPOAE frequency sweeps can be expected amongst different racial groups given that no significant differences were identified between the groups. To further define the effects of race and gender on auditory measures, future studies should include larger numbers of subjects, measurement of body size and middle ear reflectance, and examine emission generators.

Risk factors for distortion product otoacoustic emissions in young men with normal hearing.

The purpose of this study was to evaluate the possible effects of risk factors on distortion product otoacoustic emissions (DPOAEs) in young adult men with normal hearing. Four hundred thirty-six United States Marine recruit men (mean age = 19.2 years +/- 1.8 years; age range = 17-29 years) participated in this study. Questionnaires were given to each recruit to obtain demographic data and history of noise exposure, solvent exposure, smoking history, and hearing-related histories. Otoscopy, tympanometry, pure-tone air-conduction audiometry (2.0-8.0 kHz) and DPOAEs (2.3-8.0 kHz) were measured. DPOAE levels were lower in Not Hispanic or Latino recruits, in heavy smokers, in recruits who reported loud live music exposure and ringing in their ears after noise exposure. These differences were not statistically significant at all frequencies. Recruits with multiple risk factors had the lowest DPOAEs as compared to recruits with fewer, or no, risk factors; these differences were not statistically significant. Obtaining risk factor data as part of an audiometric evaluation is important even though the individual may have normal hearing.

Perception of spectral contrast by hearing-impaired listeners.

The ability to discriminate the spectral shapes of complex sounds is critical to accurate speech perception. Part of the difficulty experienced by listeners with hearing loss in understanding speech sounds in noise may be related to a smearing of the internal representation of the spectral peaks and valleys because of the loss of sensitivity and an accompanying reduction in frequency resolution. This study examined the discrimination by hearing-impaired listeners of highly similar harmonic complexes with a single spectral peak located in 1 of 3 frequency regions. The minimum level difference between peak and background harmonics required to discriminate a small change in the spectral center of the peak was measured for peaks located near 2, 3, or 4 kHz. Component phases were selected according to an algorithm thought to produce either highly modulated (positive Schroeder) or very flat (negative Schroeder) internal waveform envelopes in the cochlea. The mean amplitude difference between a spectral peak and the background components required for discrimination of pairs of harmonic complexes (spectral contrast threshold) was from 4 to 19 dB greater for listeners with hearing impairment than for a control group of listeners with normal hearing. In normal-hearing listeners, improvements in threshold were seen with increasing stimulus level, and there was a strong effect of stimulus phase, as the positive Schroeder stimuli always produced lower thresholds than the negative Schroeder stimuli. The listeners with hearing loss showed no consistent spectral contrast effects due to stimulus phase and also showed little improvement with increasing stimulus level, once their sensitivity loss was overcome. The lack of phase and level effects may be a result of the more linear processing occurring in impaired ears, producing poorer-than-normal frequency resolution, a loss of gain for low amplitudes, and an altered cochlear phase characteristic in regions of damage.

Level dependence of distortion-product otoacoustic emissions measured at high frequencies in humans.

Given that high-frequency hearing is most vulnerable to cochlear pathology, it is important to characterize distortion-product otoacoustic emissions (DPOAEs) measured with higher-frequency stimuli in order to utilize these measures in clinical applications. The purpose of this study was to explore the dependence of DPOAE amplitude on the levels of the evoking stimuli at frequencies greater than 8 kHz, and make comparisons with those data that have been extensively measured with lower-frequency stimuli. To accomplish this, DPOAE amplitudes were measured at six different f2 frequencies (2, 5, 10, 12, 14, and 16 kHz), with a frequency ratio (f2/f1) of 1.2, at five fixed levels (30 to 70 dB SPL) of one primary (either f1 or f2), while the other primary was varied in level (30 to 70 dB SPL). Generally, the level separation between the two primary tones (L1 > L2) generating the largest DPOAE amplitude (referred to as the "optimal level separation") decreased as the level of the fixed primary increased. Additionally, the optimal level separation was frequency dependent, especially at the lower fixed primary tone levels ( < or = 50 dB SPL). In agreement with previous studies, the DPOAE level exhibited greater dependence on L1 than on L2.

Acoustic reflexes to Schroeder-phase harmonic complexes in normal-hearing and hearing-impaired individuals.

Harmonic complexes generated with positive or negative Schroeder-phases may result in differences in cochlear excitation, even though their long-term spectra and amplitudes are equal. As a measure of possible differences in cochlear excitation resulting from these harmonic complexes, thresholds and growth of the acoustic reflex were assessed in normal-hearing and hearing-impaired subjects. Harmonic complexes with fundamental frequencies of 50, 100, and 200 Hz were constructed with positive and negative-Schroeder phases. In normal-hearing subjects, acoustic reflex thresholds for the 50- and 100-Hz fundamental waveforms were typically lower for negative Schroeder-phase complexes than for positive Schroeder phase stimuli. At the highest fundamental frequency of 200 Hz, there were no significant threshold differences due to phase. Hearing-impaired subjects showed a similar pattern for thresholds between the two phase selections, but with smaller differences than those observed in normal-hearing subjects. At levels above reflex threshold, the magnitude of the acoustic reflex was greater for the negative-phase than the positive-phase stimuli for the lowest fundamental frequency, but no significant differences were observed at fundamental frequencies of 100 and 200 Hz. These results are consistent with generally greater cochlear excitation in response to negative than to positive Schroeder-phase stimuli when the fundamental frequency is sufficiently low. Increased excitation may reflect a synchronization of response across a wide band of frequencies in the cochlea when the rate of frequency sweep within periods of these harmonic complexes is appropriately matched to timing characteristics of the traveling wave.